Coronary and peripheral arterial diseases are leading causes of morbidity and mortality in the US and worldwide. Principal treatments include bypass graft surgery and catheter-based procedures to open blockages (angioplasty). Angioplasty and cardiovascular surgery are also widely employed to maintain venous access for dialysis and to repair congenital cardiovascular malformations. In all cases, stenosis, fibrosis, and vessel failur are significant post-procedure problems with nearly 50% of autologous vein grafts used in peripheral or coronary artery bypass surgery failing over time due to maladaptive vessel remodeling. Vessel failures are driven to a large extent by cellular responses elicited by tissue injury during manipulation and by altered hemodynamic stresses after the re-establishment of circulation. Of principal concern, maladaptive cascades initiated by adventitial fibroblasts (AFs) residing in the exterior portion of at-risk vessels are now widely recognized as major contributors to pathogenesis in grafted and manipulated vessels. Instructive biomaterials that attenuate maladaptive cellular responses of AFs, encourage adaptation to altered hemodynamic conditions, and provide cellular material for populating a healthy neo-adventitium and vaso vasorum would have significant clinical impact resulting in decreased procedure failure rates and a potential increase in the ability to use pre-treated autologous vessels for transplantation. We thus seek to develop injectable, PEG-based polymeric biomaterials that can be placed along the exterior of at-risk vessels either prior to or just after manipulation, as a facile clinial intervention to beneficially influence AF responses and vessel remodeling. Based on extensive preliminary data indicating our ability to guide AF phenotypes with materials strategies, our three aims are to (i) determine in detail the effects of hydrogel mechanical properties on adventitial cell phenotype, (ii) evaluate the effects of critical cell signaling molecules co-delivered to cells by hydrogels, and (iii) assess the effects of hydrogels placed on target vessels in an animal model. Improving our understanding of the central mechanisms that drive adventitial cell phenotype will afford instructive materials that can reduce stenosis, attenuate fibrosis, and encourage formation of healthy vasa vasorum to improve outcomes after vascular procedures.